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We demonstrate that, in human bladder cancer, amplification of the E2F3 gene, located at 6p22, is associated with overexpression of its encoded mRNA transcripts and high levels of expression of E2F3 protein. Immunohistochemical analyses of E2F3 protein levels have established that around one-third (33/101) of primary transitional cell carcinomas of the bladder overexpress nuclear E2F3 protein, with the proportion of tumours containing overexpressed nuclear E2F3 increasing with tumour stage and grade. When considered together with the established role of E2F3 in cell cycle progression, these results suggest that the E2F3 gene represents a candidate bladder cancer oncogene that is activated by DNA amplification and overexpression.

Reduced expression of the adhesion molecule E-cadherin has been associated with increased invasiveness and poorer survival in patients with bladder cancer. We have examined soluble E-cadherin (sE-cadherin) and total protein concentrations in urine from patients with bladder cancer (n = 34), non-neoplastic benign urological diseases (n = 14) and healthy controls (n = 21) to determine their diagnostic and prognostic significance. Soluble E-cadherin concentrations of the cancer group were significantly higher (P < 0.001) than those of the controls but the benign group was not significantly different from either the cancer group or the controls. When sE-cadherin concentrations were adjusted for creatinine, similar but more statistically significant results were obtained and the benign group was significantly elevated compared with the controls (P < 0.01). No differences were apparent between the invasive (pT1-4) and non-invasive (pTa) cancers. Urinary total protein concentrations in the cancer group were significantly higher than the controls (P < 0.001) and the benign group (P < 0.05) although no difference was seen between the benign group and patients with non-invasive (pTa) cancer or between the benign group and controls. When expressed as the protein/creatinine index, results were similar but more statistically significant and a significant difference was seen between invasive and non-invasive cancers (P < 0.01). Only the protein/creatinine index correlated significantly with stage of the tumour (P < 0.01). It is concluded that urinary sE-cadherin measurements are of no greater value than urinary total protein.

Purpose: We determined the role, if any, of 1 and 5 instillations of intravesical mitomycin C in the treatment of newly diagnosed superficial bladder cancer., Materials and Methods: A multicenter randomized clinical trial was done involving 502 patients with newly diagnosed superficial bladder cancer. After complete transurethral resection patients with newly diagnosed superficial bladder cancer. After complete resection patients were randomized into 1 of 3 treatment arms: no further treatment, 1 instillation of mitomycin C at resection and 1 instillation at resection and at 3-month intervals for 1 year (total 5 instillations). The dose of mitomycin C used was 40 mg./40 ml. water. End points were interval to first superficial recurrence, recurrence rate (defined as the number of positive cystoscopies per year) and progression-free interval rate (progression defined as the development of muscle invasive or metastatic disease, or death from bladder cancer)., Results: After median followup of 7 years 1 and 5 instillations of mitomycin C resulted in decreased recurrence rates and increased recurrence-free interval. The benefit of mitomycin C was observed in patients at low, medium and high risk for subsequent recurrence. There was suggestive but not conclusive evidence that 5 instillations of mitomycin C offered a slight advantage over 1 instillation., Conclusions: Our analysis confirms the positive benefit of mitomycin C to decrease the number of subsequent recurrences and increase the recurrence-free interval.

The adhesion molecule E-cadherin is essential for maintaining epithelial intercellular adhesion. Loss or reduced expression of E-cadherin has been related to invasive behaviour in a wide range of carcinomas. Using immunoblotting techniques, the existence of multiple soluble forms of E-cadherin was demonstrated in urine from healthy volunteers and patients with benign urinary tract disorders or bladder cancer. The existence of soluble forms of E-cadherin in the urine may reflect shedding from the urinary tract epithelium as part of the normal turnover of this molecule. The possibility that enhanced shedding may contribute to the loss of E-cadherin expression/function in malignancy is discussed.

This double-blind randomised phase III trial was designed to assess the effect of pyridoxine administration on the recurrence of Ta and T1 transitional cell tumours of the bladder. The trial accrued 291 patients and showed no significant difference between the pyridoxine and placebo treatment groups with respect to the time to first recurrence or the recurrence rate. Adjustment for the main prognostic factors, namely the recurrence rate prior to entry, the number of tumours at entry, the G grade and the levels of the tryptophan metabolites kynurenine plus acetyl kynurenine at entry do not change the overall conclusions.

Multiple cavitary pulmonary metastases from bladder carcinoma are rare. We present a case of superficial transitional cell carcinoma of the bladder with multiple cavitating lung secondaries treated by systemic chemotherapy.

A famous surgeon observed that the most important instrument for the management of superficial bladder cancer was a typewriter because it facilitated the organisation of the regular follow up examinations that are so important in controlling this disease. Cystoscopic follow up must be lifelong, and the cost, in the broadest sense, to both patient and health service is considerable. A recent study has suggested that the conventional frequency of bladder examinations may not be necessary and that most patients could be spared many cystoscopies. Instillation of cytotoxic drugs in the bladder has been shown to reduce the recurrence of tumours destroyed endoscopically and the development of new tumours elsewhere in the bladder. Because intravesical instillations are inconvenient, expensive, and may be toxic they have been reserved for patients thought to be at greatest risk of recurrence. However, two clinical trials have shown that a single cytotoxic instillation may be beneficial for low risk patients. If this is verified in everyday practice, the routine use of intravesical chemotherapy for all patients at the time of initial treatment could reduce the need for cystoscopies even further. Such changes should improve the quality of life of the 7000 new patients with superficial bladder cancer each year in England and Wales and allow savings to be made in the NHS.

Forty patients with multiple recurrent superficial bladder tumours received an 8-week course of weekly instillations of 4' epirubicin 30 mg in 50 ml saline. The overall response rate was 58% and side effects were minimal.

Fifty-seven patients with transitional cell carcinoma of the bladder, categories pT2, pT3a and pT3b, were treated by transurethral resection of the tumour mass (54 cases) or partial cystectomy (3 cases) followed by 8 doses of methotrexate 2 g i.v. every 3 weeks with appropriate Leucovorin rescue. At completion of chemotherapy 6 months after TUR 33/57 patients were tumour-free; 5/57 had new superficial tumours; 13/57 had persistent tumour invading muscle, 3 showed tumour progression and 3 had died from treatment complications. One-year survival was 45/57 (82%); 2-year survival was 23/39. Although some patients developed metastases and others have grown new superficial tumours, of those surviving, the bladder was free of the original invasive tumour in 38/45 (84%) at 1 year and in 19/24 (79%) at 2 years. It is concluded that transurethral resection plus high dose methotrexate may offer an effective alternative to radiotherapy or cystectomy for a significant proportion of patients with invasive bladder cancer.

Twenty-three patients who were given intravesical Mitomycin C for treatment of superficial bladder cancer have been followed up for a further 12 and 24 months after an initial assessment 5 weeks after completing therapy. At 5 weeks 17 (74%) showed complete disappearance of tumour and 4 (17%) showed a partial response. Twelve months later 8 (35%) remained tumour-free and 15 (65%) had recurrences; 5 of these (22% of all patients) had progressed to invasive cancer. The results at 24 months were little different except that one further patient (27% in all) progressed to invasive cancer. Six patients with symptomatic carcinoma in situ became symptom-free after Mitomycin C, but despite remaining free of symptoms three have progressed to invasive cancer. This small series shows that involvement of large areas of bladder urothelium by tumour, carcinoma in situ and previous therapy for tumour are unfavourable prognostic indices.

Radical radiotherapy alone has been compared with radical radiotherapy followed by chemotherapy using doxorubicin (Adriamycin) and 5-fluorouracil in a randomised prospective study on 129 patients presenting with T3, NX, MO transitional cell carcinoma of the bladder. One hundred and ten patients were evaluable with a minimum follow-up of 2 years. The addition of this form of chemotherapy did not appear to influence the survival rate or the proportion of patients free from tumour. It cannot be recommended for routine use in the primary treatment of infiltrating bladder cancer.

Of 48 patients with bladder tumors treated with intravesical epodyl 17 have shown a complete remission at some stage of treatment, although several have relapsed later. Partial remission occurred in 20 patients and 11 have shown no improvement or the lesions have progressed. Epodyl is used best as an adjunct to transurethral resection or diathermy of T1 bladder lesions. Even in patients who do not show complete remission epodyl may reduce the incidence of recurrence and the number of lesions. It is useful when rapid recurrence of T1 bladder tumors prevents control by resection or diathermy and it also is beneficial as an emergency measure to control hematuria. Complications are not infrequent and may be severe occasionally. Bone marrow depression has been seen in 2 patients whose bladders showed extensive carcinoma in situ.

52 patients with advanced bladder cancer, no longer controlled by conventional therapy, have been treated by combination chemotherapy with Adriamycin and 5-fluorouracil. The objective remission rate has been 40%. The morbidity of the chemotherapy has not been excessive. The response has not been related to the histological grade of the primary tumour and previous treatment. Patients with a good performance status (Karnofsky index) have responded better than those with a poor performance status.

Intravesical chemotherapy has been shown to prolong the interval free of disease and to reduce the tumor recurrence rates in patients with superficial bladder cancer. These observations led us to consider whether a course of intravesical chemotherapy might provide a long-term decrease in the recurrent tumor rate or reduce the incidence of progression to invasive carcinoma. The records of 123 patients entered into a randomized multicenter protocol between 1975 and 1978 were examined. Patients had received a 1-year course of thiotepa or VM26, or transurethral resection alone. Mean followup was 47 months. Patients receiving thiotepa or VM26 had a lower rate of tumor recurrence, expressed as recurrences per 100 patient-months, than those undergoing transurethral resection only (5.25 versus 5.71 versus 7.98) but this was not statistically significant. However, 28 per cent of the controls required therapy besides transurethral resection to control the bladder cancer and 19 per cent died of advanced bladder cancer during followup. Only 15 per cent of the patients undergoing intravesical chemotherapy required therapy other than transurethral resection and only 3 per cent died of advanced carcinoma of the bladder. This finding suggests that intravesical chemotherapy given for 1 year is associated with a significant decrease in the incidence of tumor progression, and provides the justification to conduct future trials with extended followup.

Twenty-three patients with histologically proven superficial bladder cancer (Tis, Ta, T1) were treated with intravesical instillations of Mitomycin C at a dose of 20 mg in 20 ml of water 3 times weekly for 21 instillations. Seventeen patients (77%) showed complete disappearance of all known disease and a further 4 showed partial responses. In 8 patients toxic effects developed (thrombocytopaenia 1, chemical cystitis 2, skin rash 3, urinary tract infection 2). All resolved rapidly on stopping the treatment but were severe enough in 5 patients to prevent them from receiving a full course of treatment.

Cytotoxic chemotherapy is used increasingly in the management of bladder cancer. The agents used, intravesically and systemically, are reviewed, together with preliminary reports of certain trials of adjuvant chemotherapy that have now been activated.

A randomised control trial of intravesical instillation of mitomycin C was conducted in 457 patients with cancer of the bladder that was confined to the submucosa on histological examination. The events studied were the recurrence free rate, the recurrence rate/year, and the number of new tumours developing/year. At the initial cystoscopy the tumours were completely resected and the patients randomised to have no instillation of mitomycin C, a single instillation of 40 mg in 40 ml of water at that cystoscopy, or a single instillation and then four further instillations. All patients had follow up cystoscopies every three months for the first year, twice in the second year, and yearly thereafter. After a median of 12 months, follow up information was available for 397 patients. Patients receiving both the single instillation of mitomycin C and the instillations at five cystoscopic examinations had significantly lower yearly recurrence rates and tumour rates than those in the control group, and the group receiving multiple instillations fared significantly better than those receiving a single instillation. The figures on progression to invasive cancer were too small to allow conclusions to be drawn.

Forty-three patients with recurrent multiple superficial bladder tumours (Tis, Ta and Tl) were treated with Mitomycin C 20 mg in 20 ml water intravesically weekly for 8 to 12 weeks, and monthly instillations were continued for 5 to 6 months. Residual tumour was resected at 12 weeks, at which time 40 patients (93%) showed a response to treatment. A complete response was seen in 24 (56%) and 16 (37%) showed a partial response. After a follow-up of 12 to 48 months (median 19), 19 of 33 evaluable patients (58%) have shown tumour recurrence. Invasive tumour has developed in seven (17%) and transitional cell tumours of the ureter in two of those patients who showed an initial response to treatment.

The cytotoxic drug combination of adriamycin and 5-fluorouracil has resulted in a 35% objective response in 20 patients with advanced bladder cancer. This has been achieved with minimal toxicity and on an out-patient basis. If the survival rate of patients with invasive bladder cancer is to be improved it seems likely that some form of systemic treatment will need to be added to the local measures currently in use. Further studies of different chemotherapeutic agents should help to define an effective and safe form of adjunvant therapy.